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WO2019186260A1 - Procédé amélioré pour la préparation de sitagliptine et de sels pharmaceutiquement acceptables de celle-ci - Google Patents

Procédé amélioré pour la préparation de sitagliptine et de sels pharmaceutiquement acceptables de celle-ci Download PDF

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Publication number
WO2019186260A1
WO2019186260A1 PCT/IB2018/059746 IB2018059746W WO2019186260A1 WO 2019186260 A1 WO2019186260 A1 WO 2019186260A1 IB 2018059746 W IB2018059746 W IB 2018059746W WO 2019186260 A1 WO2019186260 A1 WO 2019186260A1
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acid
solvents
compound
mixture
formula
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PCT/IB2018/059746
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English (en)
Inventor
Goverdhan Gilla
Swapnil Surendra Mohile
Sandeep TAPKIR
Sachin Ambadas Dawange
Abhijit Omprakash Bajaj
Shekhar Yashawant Gujar
Sudhir Nambiar
Amit Kumar Tiwari
Mukesh Vyankatkrishnamurti Samal
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Hikal Ltd
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Hikal Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to an improved and commercially viable process for preparation ofsitagliptin and pharmaceutically acceptable salts thereof in high yield with high chemical and chiral purity.
  • Sitagliptin is chemically known as (A ) - 3 - a m i n o - 1 - [ 3 - (t ri fl u o ro m c t h y 1 ) - 5 , 6 , dihydro [1,2,4] triazolo[4,3-a] pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl) butan-l-one and useful as a potent second-generation inhibitor of dipeptidyl -peptidase (DPP) IV for the treatment of Type-2 diabetes.
  • DPP dipeptidyl -peptidase
  • Sitagliptin is first disclosed in US Patent 6,699,871 and can be synthesized by different synthetic approaches as mentioned below.
  • the first synthesis of sitagliptin appears to be set out in PCT patent publication WO 2003/004498 (henceforth '498).
  • the said PCT'498 discloses a method of introducing a chiral-amine group using a chiral pyrazine derivative and to prepare sitagliptin by Arndt-Eistert homologation using t-butoxylcarbonylamino-4-(2,4,5- trifluorophenyl)-butyric acid as a sitagliptin intermediate.
  • the said process is represented in scheme (I), which involves the use of unusual dihydropyarazine chiral promoters, diazomethane and silver salt which are not preferred reagents for industrial synthesis.
  • the PCT Publication W02004/087650 discloses the preparation of sitagliptin using the chiral benzyloxylazetidinone as an intermediate.
  • the said PCT‘378,‘733 and‘l5l discloses the preparation of sitagliptin, which involves an enantioselective reduction of the intermediate chiral enamine in the presence of specific catalysts and the PCT Publication W02009/085990 discloses the preparation of sitagliptin using various chiral auxiliaries, as a chiral resolving agent.
  • the methods disclosed in above PCT Publications are useful for preparing sitagliptin, an alternative method of the preparation, particularly for manufacturing scale production are desirable.
  • the PCT Publication WO 2015120111 discloses the preparation of sitagliptin and its pharmaceutically acceptable salt by preparing enamide compound of formula (II), reacting with Michael donar compound of formula (III).
  • Scheme5 discloses the use ofl-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)-4(2,4,5trifluorophenyl)butane-l,3-dione for the preparation of enamide compound (formula II) on reacting with Michael donor compound formula (III) [(R)-phenyl ethyl amine, (lR)-l- carboxamidophenylmethanamine] to produce the compound of formula (VUIb) which on deprotection produces sitagliptin and its pharmaceutically acceptable salt.
  • IP.com Journal, Vol.9, Iss.5B, Page 36, 2009 discloses the novel process for the preparation of sitagliptin by reacting l-(3-(trifluoromethyl)-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-l,3-dione with optically pure(S)-phenylethylamine (which may be substituted with an alkyl or alkoxy group on phenyl ring) in the presence of a drying agent to obtain (Z)-3-(l-phenylethylamino)-l-(3- (trifluoromethyl)-5,6-dihydro-[l,2,4] triazolo[4,3-a] pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl)but-2-en-l-one
  • the main objective of the present invention is to provide an improved process for the preparation of a compound of formula (I), which is simple, economical, user-friendly and commercially viable.
  • Another objective of the present invention is to provide a process for the preparation of a compound of formula (I) and its pharmaceutically acceptable salts with a greater yield and higher chiral and chemical purity, which would be easy to implement on commercial scale and makes the present invention eco-friendly as well.
  • Another objective of the present invention is to provide a process for the preparation of a compound of formula (I) and its pharmaceutically acceptable salts by exploring the use of substituted (S)-phcnyl glycine ester or its salts or its derivatives as a chiral auxiliary.
  • Yet another objective of the present invention is to provide a process for the preparation of a compound of formula (I), and its pharmaceutically acceptable salts in a high yield, with high chiral and chemical purity using economical, inexpensive chiral auxiliary substituted ( S )- phenyl glycine ester or its salts or its derivatives and keto amide as a key starting material.
  • the present invention provides an improved process for the preparation of sitagliptin of formula (I) and pharmaceutically acceptable salts thereof;
  • the present invention provides an improved process for the preparation of sitagliptin of formula (I) and salt thereof via novel synthetic approach.
  • the present process for the preparation of sitagliptin of formula (I) comprises reacting of compound of formula (II) with compound of formula (III) to obtain compound of formula (IV) followed by reduction in presence of suitable reducing reagent to obtain compound of formula (V) and further hydrogenation in presence of suitable catalyst to obtain compound of formula (I).
  • the compound of formula (IV) of step (a) is obtained by reacting compound of formula (II) with chiral compound of formula (III) such as substituted (S)-phcnylglycinc esters or its salts or its derivatives.
  • substituent“X” is Ci-C 6 alkyl chain, branched, substituted and unsubstituted aliphatic or aromatic ring or any halide substituent’s (halide may be of any noi. e. 1 to 5) and “R” is selected from the group consisting of C i -C 6 alkyl chain, branched, substituted and unsubstituted aromatic ring in presence of suitable acid in a suitable solvent at a suitable temperature.
  • step (a), step (b) and step (c) is selected from group consisting of water, alcoholic solvents, ketonic solvents, esters, halogenating solvents, ethereal solvents, hydrocarbon solvent and the like or mixture of solvents.
  • step (b) and step (c) is selected from group consisting, aprotic solvent and the like or mixture of solvents.
  • step (a), step (b) and step (c) are alcoholic solvents such as methanol, ethanol, isopropanol, n- propanol, «-butanol and the like; or mixture of solvents.
  • the said solvent used in step (a), step (b) and step (c) the ketonic solvents such as acetone, methyl isobutyl ketone, ethyl methyl ketone and «-butanone and the like; or mixture of solvents.
  • the said solvent used in step (a), step (b) and step (c) the halogenating solvents such as ethylene dichloride, chloroform, dichloromethane and the like; or mixture of solvents; more preferably dichloromethane.
  • step (a), step (b) and step (c) esters used such as ethyl acetate, «- propyl acetate and isopropyl acetate and the like; or mixture of solvents.
  • step (a), step (b) and step (c) ethereal solvents such as methyl tert-butyl ether, l,4-dioxane, tetrahydrofuran, l,2-dimethoxy ethane and the like or mixture of solvents, more preferably l,2-dimethoxy ethane.
  • ethereal solvents such as methyl tert-butyl ether, l,4-dioxane, tetrahydrofuran, l,2-dimethoxy ethane and the like or mixture of solvents, more preferably l,2-dimethoxy ethane.
  • step (a), step (b) and step (c) hydrocarbon solvents such as cyclohexane, «-hexane, «-heptane, toluene, xylene and the like or mixture of solvents, more preferably toluene.
  • step (b) and step (c) is preferably selected from N,N-dimethylformamide, dimethylsulfoxide and dimethyl acetamide and the like or mixture of solvents.
  • step (a) is preferably selected from group consisting of organic acid, inorganic acid and the like or mixture of acids, more preferably inorganic acids.
  • the said acid of step (a) is organic acid such as acetic acid and propionic acid
  • the inorganic acid such as cone hydrochloric acid, cone sulfuric acid, nitric acid, phosphoric acid, and the like or mixture of acids, more preferably cone sulfuric acid.
  • the suitable temperature may be preferably carried out at low to ambient temperature or to reflux temperature; more preferably at ambient to reflux temperature and the reaction is performed under atmospheric distillation or reduced pressure distillation of solvent.
  • the said reducing agent of step (b) is preferably selected from group consisting of suitable metal catalyst, such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminium hydrides, sodium cyanoborohydride, sodium triacetoxyborohydride, platinum oxide, palladium on carbon and the like mixture of catalyst, more preferably sodium borohydride.
  • suitable metal catalyst such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminium hydrides, sodium cyanoborohydride, sodium triacetoxyborohydride, platinum oxide, palladium on carbon and the like mixture of catalyst, more preferably sodium borohydride.
  • step (b) wherein the said acid of step (b) is preferably selected from group consisting of methane sulphonic acid, trifluroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, pyridine sulfonic acid, camphor sulfonic acid, concentrated hydrochloric acid, zinc chloride or in combination of these mixture of acids, more preferably methanesulfonic acid.
  • step (b) wherein the said temperature used in step (b) may be preferably carried out at low temperature to ambient temperature.
  • step (a) and step (b) wherein all the crude involved in step (a) and step (b) is used as such or is purified by distillation or crystallization or by different purification techniques well understood by those skilled in the art.
  • the hydrogenating catalyst used in step (c) is preferably selected from palladium on carbon, palladium hydroxide on carbon, nickel on carbon and the like or mixture of catalysts, more preferably palladium on carbon.
  • step (c) wherein the acid used in step (c) is selected from organic or inorganic acids.
  • step (c) wherein the base used in step (c) is selected from organic or inorganic or aromatic bases.
  • the said temperature used in step (c) may be preferably carried out at low to ambient temperature or to reflux temperature; more preferably at ambient to reflux temperature.
  • a compound of formula (I) may be further converted into its pharmaceutically acceptable salts formula (VI) by treating with a suitable acid, more preferably hydrochloric acid.
  • salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure and may also be in the form of hydrates.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine.
  • basic ion exchange resins such as arginine
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric and tartaric acids.
  • the process of the present invention avoids excess usages of reagent(s) and organic solvent(s), thereby promoting green chemistry and ensuring a cleaner surrounding by putting less load on environment. 7)
  • the process of the present invention involves the solvents, which can be recycled and reused thereby makes the process more economical, industrially and commercially viable.
  • the crude compound (I) (l.Oeq) was added into isopropyl alcohol (13.0V), stirred for 5 min. and cone hydrochloric acid (0.4V) was added.
  • crystals of sitagliptin hydrochloric acid (l%w/w) with chiral purity more than 99.85% was added and cooled to 0°C to 5°C.
  • the reaction mixture was heated to 75°C to 85°C till clear solution observed.
  • the reaction mixture was allowed to cool to 20°C to 25°C gradually and stirred for lh.
  • the solid compound was filtered, washed with isopropyl alcohol (2V) and further dissolved into water (5V) and pH of solution was maintained more than 9.0 using 1N sodium hydroxide solution.
  • Stage- 1 A To a stirred solution of dichloromethane (2.8L), compound II (200g, 2.03moles) and compound III (137. lOg, 0.687moles) added cone sulfuric acid (4.8g, 0.0489 moles) and heated the reaction mixture to reflux at 39 °C for 3 h. The solvent was removed by distillation from reaction mixture under reduced pressure till minimum stirrable volume. After completion of reaction, the reaction mixture was allowed to cool to 25°C to 30°C. The reaction mixture was quenched by water, stirred for 30 min. and the aqueous and organic layer were separated. The organic layer was washed with aq.
  • Stage-lB To a stirred precooled solution of dichloromethane (0.7L), l,2-dimethoxy ethane (0.7L) and sodium borohydride (l9.46g, 0.5144 moles) at -55°C to -75°C, methanesulphonic acid (85mL, 1.309 moles) was added slowly at -55°C to -75°C and reaction mixture was stirred and maintained for 2h.
  • Stage- 1C To a methanolic solution of compound V (275.0 g on dry basis, 0.466 moles) and methanol (1.0 L) in a 2.0 L hydrogenator, 10% palladium on carbon (14.0 g) was added and stirred under 10 to 14 Kg of hydrogen pressure. The reaction mixture was heated at 60°C to 65°C for 8h. After completion of reaction the reaction mixture was allowed to cool to 20°C to 30°C, filtered on celite bed and bed was washed with methanol. The solvent was evaporated under reduced pressure till minimum stirrable volume remains in reaction mass. To the above reaction mass, charged fresh isopropyl alcohol (2.2L) and cone.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé amélioré pour la préparation de sitagliptine (I) et ses sels pharmaceutiquement acceptables, qui est simple, économique, efficace, convivial et respectueux de l'environnement, de plus commercialement viable.
PCT/IB2018/059746 2018-03-28 2018-12-07 Procédé amélioré pour la préparation de sitagliptine et de sels pharmaceutiquement acceptables de celle-ci Ceased WO2019186260A1 (fr)

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IN201821011626 2018-03-28
IN201821011626 2018-03-28

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WO2019186260A1 true WO2019186260A1 (fr) 2019-10-03

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004085661A2 (fr) * 2003-03-24 2004-10-07 Merck & Co., Inc Procede de synthese de derives d'acides amines beta chiraux
WO2011060213A2 (fr) * 2009-11-12 2011-05-19 Dr. Reddy's Laboratories Ltd. Préparation de la sitagliptine et de ses sels
US20170183351A1 (en) * 2014-02-05 2017-06-29 Stereokem, Inc. Expedient synthesis of sitagliptin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004085661A2 (fr) * 2003-03-24 2004-10-07 Merck & Co., Inc Procede de synthese de derives d'acides amines beta chiraux
WO2011060213A2 (fr) * 2009-11-12 2011-05-19 Dr. Reddy's Laboratories Ltd. Préparation de la sitagliptine et de ses sels
US20170183351A1 (en) * 2014-02-05 2017-06-29 Stereokem, Inc. Expedient synthesis of sitagliptin

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